Dithiocarbonylthioacetyl cephalosporins

ABSTRACT

R1 is hydrogen, lower alkyl or cyclo-lower alkyl; R2 is a salt forming metal, lower alkyl or cyclo-lower alkyl; R3 is lower alkyl or phenyl-lower alkyl; and X is hydrogen, hydroxy or lower alkanoyloxy, are useful as antibacterial agents.   wherein R is hydrogen, lower alkyl, trimethylsilyl alkali metal or   Dithiocarbonylthio cephalosporin derivatives of the formula

United States Patent [191 Treuner et al.

[ Dec. 16, 1975 DITHIOCARBONYLTHIOACETYL CEPHALOSPORINS [75] Inventors: Uwe D. Treuner, Regensburg;

Hermann Breuer, Burgweinting, both of Germany [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Apr. 29, 1974 [21] Appl. No.: 465,013

Related US. Application Data [60] Division of Ser. No. 272,228, July 17, 1972, Pat. No. 3,846,418, which is a continuation-in-part of Ser. No. 180,523, Sept. 14, 1971, abandoned.

Sassiver, et al., Semisynthetic Cephalosporins, Antimicrobial Agents and Chemeotherapy; 1968, ed. Hobby, (1969), pp. 101-108.

Lewis, et al., Semisynthetic Cephalosporins, Antimicrobial Agents and Chemeotherapy, (1968, ed. l-Iobby, (1969), pp. 109-114.

Primary Examiner-Nicholas S. Rizzo Assistant ExaminerDiana G. Rivers Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith [57] ABSTRACT Dithiocarbonylthio cephalosporin derivatives of the formula wherein R is hydrogen, lower alkyl, trimethylsilyl alkali metal or If CH O -C-R R is hydrogen, lower alkyl or cyclo-lower alkyl; R is a salt forming metal, lower alkyl or cyclo-lower alkyl; R; is lower alkyl. or phenyl-lower alkyl; and X is hydrogen, hydroiky or lower alkanoyloxy, are useful as antibacterial agents.

. GIaimS, No Drawings DITHIOCARBONYLTHIOACETYL CEPHALOSPORINS This application is a division of application Ser. No. 5 272,228, filed July l7, I972, US. Pat. No. 3,846,418, issued Nov. 5, 1974 which in turn is a continuation-inpart of application Ser. No. 180,523, filed Sept. 14, 1971, now abandoned.

SUMMARY OF THE INVENTION This invention relates to new dithiocarbonylthioacetylcephalosporins of the formula R represents hydrogen, lower alkyl, aralkyl, tri-( lower alkyl)silyl, a salt forming ion or the group especially hydrogen, methyl, pivaloyloxy, sodium or potassium; R is hydrogen, lower alkyl, phenyl, thienyl, furyl, oxazolyl, isoxazolyl or thiazolyl, especially phenyl; R is lower alkyl, especially methyl or ethyl; R is lower alkyl, preferably methyl or t-butyl and X is preferably hydrogen or acetoxy.

DETAILED DESCRIPTION OF THE INVENTION The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.

The cycloaliphatic groups are the four to six carbon alicyclics cyclobutyl, cyclopentyl and cyclohexyl as well as the monounsaturated and diunsaturated four to six carbon rings. The five and six carbon rings are preferred in each series with the l,4-cyclohexadienyl group being especially preferred.

The aryl groups are monocylic carbocyclic aryl groups including simply substituted members. By way of illustration, this includes the phenyl ring and simply substituted phenyl containing one to three substituents (preferably only one) such as the halogen (chlorine and bromine being preferred), lower alkyl groups such as those defined above, lower alkoxy groups, (i.e., lower alkyl groups of the type defined above attached to an oxygen), hydroxy, carboxy and the like. In the case of the last two named substituents there is preferably only one, especially in the para position of the phenyl. Illustrative are phenyl, 0-, m and p-chlorophenyl, 0-. mand p-bromophenyl, 3.4-dichlorophenyl, 3,5-dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl, p-hydroxyphenyl, p-carboxyphenyl and the like.

The aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. Illustrative are benzyl, o-, mor pchlorobenzyl, 0-,m- 0r p-bromobenzyl, o-, mor pmethylbenzyl, phenethyl; p-chlorophenethyl, 3,5-diethylbenzyl, 3,4,5-trichlorobenzyl and the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters. The lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above. The lower alkanoyloxy group include. for example, acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups are derived from monocyclic carbocyclic aryl groups of the kind described. Similarly I the aralkanoyloxy groups consist of monocyclic carbocyclic aryl and alkanoyloxy radicals of the type described. X also represents the radical of an amine, e.g., an alkylamine like methylamine, ethylamine, dimethylamine, triethylamine, aralkylamine like dibenzylamine, N,N'-dibenzylpyridinium, pyridinium, l-quinolinium. l-picolinium, etc. X and R may also join together. as indicated above, to form a bond linking carbon and oxygen in a lactone ring.

The heterocyclic groups represented by R are 5- to 6-membered monocyclic heterocyclic radicals (exclusive of hydrogen), including thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl, as well as these heterocyclics with the substituents halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.

The salt forming ions represented by R and R may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, dibenzylamine, N,N-dibenzylethylenediamine. methylamine, triethylamine, procaine, N-ethylpiperidine, etc.

The new dithiocarbonylthioacetylcephalosporins of this invention are produced by reacting a 7-aminocephalosporanic acid compound of formula II [which includes ,7-aminocephalosporanic acid (7-ACA). 7- amino-3-desacetoxycephalosporanic acid (7.-ADCA) and other darivatives] of the formula with a dithiocarbonylthioacetic acid of the formula (llll R.iHCOOH or an activated derivative of the former (ll). The symbols have the meanings already defined.

The activated derivatives refered to include, for example, the reaction product with an anhydride forming reagent such as ethylchloroformate, benzoyl chloride. pivaloyl chloride, etc., or with bis-imidazolecarbonyl, dicyclohexylcarbodiimide, p-nitrophenol or the like.

The reaction between 7-aminocephalosporanic acid compound and the dithiocarbonylthioacetic acid may be effected, for example, by dissolving or suspending the latter in an inert organic solvent such as chloro form. methylene chloride, dioxane, benzene or the like. and adding. at about room temperature or below, about an equimolar amount of an anhydride forming reagent, e.g.. ethyl chloroformate, benzoylchloride or the like, or other activating compound such as dicyclohexylcarbodiimide, along with a salt forming organic base, such as triethylamine, pyridine or the like. followed. after an interval. by the addition of the 7-aminocephalosporanic acid compound. The product of the reaction is then isolated by conventional procedures. e.g.. by concentration or evaporation of the solvent.

When R is the acyloxymethyl group this group may be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the dithiocarbonylthioacetic acid or the activated derivative by treatment with one to two moles of a halomethyl ester of the formula (IV) halCH OCOR;,

wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane. benzene or the like, at about ambient temperature or below.

As an alternative, a product of formula may be produced by reacting a salt, e.g.. an alkali metal salt. of the formula with a compound of the formula S n cn-co-mr 1 l l 2 (v1) H-CH x hal l: 2

or derivative thereof in a solvent such as dimethylformamide. Me represents a metal. hal is halogen, preferably chlorine or bromine and R and R are the same as above.

The dithiocarbonylthioacetic acid of formula Ill may be produced according to the following general method:

by a procedure analogous to that described by Bonner. Jour. Org. Chem. 33, l83l (i968).

The symbols have the meanings already defined.

Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in different optically active forms. The various stereoisomeric forms as well as the racemic mixtures are within the scope of the invention.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salnwnella sc/zottmuelleri, Pseudomumls aeruginusa, Proteus vulgar-is, Escherichia coli and Streptococ- (us1) \'0genes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g.. 5.0 mg./kg, in mice.

Oral forms give prompt high blood levels which are maintained for relatively long periods.

Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

They may also be used in cleaning or disinfecting compositions. e.g., for cleaning barns or dairy equipment. at a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying. They are also useful as nutritional supplements in animal feeds.

The following examples are illustrative of the invention. A11 temperatures are on the centigrade scale.

Additional variations may be produced in the same manner by appropriate substitution in the starting material.

EXAMPLE 1 D.L-7-[ 2-[ Ethylthio )thiocarbonyl ]thiol-Z- phenylacetamido]-cephalosporanic acid salt 3.6 g. mmol.) of DL-7-a-(bromophenylacetamido)cephalosporanic acid are dissolved in ml. of absolute dimethylformamide and then 1.8 g. (10 ml.) of potassium ethyltrithionate, dissolved in 15 ml. of dimethylformamide are added with stirring. The temperature is controlled by cooling so that the mixture does not go above 40. After 10 minutes, the reaction solvent is poured into 350 ml. of cold water and extracted twice with 200 ml. of ethyl acetate each time. The ethyl acetate extract is dried with sodium sulfate and distilled off in vacuo. The oily residue is crystallized by treatment with ether and petroleum ether. The product, DL-7-[2-[[(ethylthio)thiocar bonyl ]thio -2-phenylacetamido ]cephalosporanic acid, is obtained in 83% yield; m.p. 77 -8(). Solution of the acid in a small amount of n-butanol, addition of an equivalent amount of potassium 2-ethy1hexanoate and then adding ether gives the potassium salt as a pale yellow powder. m.p. 148 (dec.). The sodium salt is formed similarly.

potassium 7 6 The following additional products are similarly obtained (melting points are for salt):

7-[2-[ methylthio )thiocarbonyllthio 1-2- phenylacetamido]-cephalosporanic acid and potas- 5 sium salt. m.p. 153 (dec.).

' 7-[2-[ (cyclohexylthio)thiocarbonyl]thio]-2- phenylacetamidol-cephalosporanic acid and potassium salt (hydrate). m.p. 143 (dec.).

-7-[2-[ ethylthio )thiocarbonyl]thioacetamido ]cephalosporanic acid and potassium salt. m.p. 140.

7-[ 2- n-butylthio )thiocarbonyl ]thioacetamido]- cephalosporanic acid and potassium salt, m.p.

7-[ 2 cyclohexylthio )thiocarbonyl ]thioacetamido cephalosporanic acid and potassium salt. m.p.

7-[ 2-[ methylthio )thiocarbonyl]thioacetamido cephalosporanic acid and potassium salt. m.p. 142.

7-[2 -[(benzylthio)thiocarbonyl]thioacetamido]- cephalosporanic acid and potassium salt. m.p. 140.

7-[2-[ (benzylthio )thiocarbonyl thio ]-2- phenylacetamido]-cephalosp0ranic acid and potassium salt, m.p. 133.

The following additional products having the formula (c) in the table are obtained by the procedure of Example 1 by substituting for the DL-7-a-(bromophenylacetamido)cephalosporanic acid. the starting material (a). and for the potassium ethyltrithionate. the starting material (b) with the substituents indicated in the table:

l ABLli-LfillllllllCtl l'mmple R R- R,

15 (Hjll (((Ho (.,H, (.H, H m SUCH), n-hut \l H 1' H oc'ocH,

m H (1H,, ococH,

19 K (H. H

20 D. cm, H

2: H D- Q ococH,

21 H I 0H, ocotH,

R, is hydrogen. lower alkyl or C C cyclolower alk \'l: zia'z' a at What IS Claimed ls: R, is aluminum alkali met il (1' ll\ iline e irth mLlll lower alkvl or C C cvclo-lower all l; R, is lower alkvl l. A compound of the formula or phenyl-lower alkyl: and X is-hydrogen. hydroxy or lower alkanoyloxy. 5 2. A com ound as in claim I wherein R, is h\'dro en g R, H CONH- H(|H (]H. or lower alkyl; R, is lower alkyl; R;, IS lower alkyl: and

X is hvdrogen or acetoxv. SR l\ t-cH -x B 3. A compound as in claim 1 wherein R and R, each 0 is hydrogen: R is lower alkyl; and X is acetoxy.

4. A compound as in claim 3 wherein the lower alkyl wherein R is hydrogen. lower alkyl. trimethylsilyl alkali metal or group is ethyl.

5'. A compound as in claim 3 wherein the lower alkyl group is n-butyl.

6. A compound as in claim I wherein R and R, each is hydrogen; R is cyclo-lower alkyl and X is acetoxy.

7. A compound as in claim 6 wherein the cyclo-lower alkyl group is cyclohexyl.

8. A compound as in claim 3 wherein the lower alkyl group is methyl. 

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R1 is hydrogen or lower alkyl; R2 is lower alkyl; R3 is lower alkyl; and X is hydrogen or acetoxy.
 3. A compound as in claim 1 wherein R and R1 each is hydrogen; R2 is lower alkyl; and X is acetoxy.
 4. A compound as in claim 3 wherein the lower alkyl group is ethyl.
 5. A compound as in claim 3 wherein the lower alkyl group is n-butyl.
 6. A compound as in claim 1 wherein R and R1 each is hydrogen; R2 is cyclo-lower alkyl and X is acetoxy.
 7. A compound as in claim 6 wherein the cyclo-lower alkyl group is cyclohexyl.
 8. A compound as in claim 3 wherein the lower alkyl group is methyl. 